Summary Basis of Decision for Zytiga ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
ZytigaTM
Abiraterone acetate, 250 mg, Tablets, Oral
Janssen Inc.
Submission control no: 138343
Date issued: 2012-02-21
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02371065
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 27, 2011, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product, Zytiga™.
Zytiga™ contains the medicinal ingredient abiraterone acetate which is an androgen biosynthesis inhibitor.
Zytiga™ is indicated with prednisone for the treatment of metastatic prostate cancer (castration-resistant prostate cancer) in patients who have received prior chemotherapy containing docetaxel. Zytiga™ functions by selectively inhibiting the 17α-hydroxylase/C17, 20-lyase (CYP17) enzyme involved in testosterone production in testicular, adrenal and prostatic tumour tissues. Inhibiting testosterone production can slow down the growth of prostate cancer.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Zytiga™ was primarily established on one randomized, double-blind, placebo-controlled, multicentre Phase III study in patients with metastatic prostate cancer (castration-resistant prostate cancer) who had received prior chemotherapy containing docetaxel. Patients continued to be treated with a GnRH agonist during study treatment, or were previously treated with orchiectomy. A total of 1,195 patients were randomized 2:1 to receive either Zytiga™ 1 gram daily in combination with low dose prednisone 5 mg twice daily [number (n) = 797], or to receive a placebo and low dose prednisone 5 mg twice daily (n = 398). A median of 8 cycles (32 weeks) were administered in the Zytiga™ treatment group compared to 4 cycles (16 weeks) in the placebo group. Overall survival was longer in the Zytiga™ treatment group with Zytiga™-treated patients having a median survival of 14.8 months compared to 10.9 months for placebo-treated patients. An updated survival analysis demonstrated a median survival of 15.8 months in the Zytiga™ treatment group compared to 11.2 months for placebo-treated patients. Sub-group analyses also showed a consistent favourable survival effect for Zytiga™-treated patients.
Zytiga™ (250 mg, abiraterone acetate) is presented in tablet form. The recommended dose of Zytiga™ is 1 gram (four 250 mg tablets) as a single daily dose that must be taken on an empty stomach. No solid or liquid food should be consumed for at least two hours before the dose of Zytiga™ is taken and for at least one hour after the dose of Zytiga™ is taken. The tablets should be swallowed whole with water. Zytiga™ is used with low-dose prednisone. The recommended dosage of prednisone is 10 mg daily. Patients started on Zytiga™ who were receiving a gonadotropin-releasing hormone (GnRH) agonist should continue to receive it. Serum transaminases and bilirubin should be measured prior to starting Zytiga™ treatment, and continued to be measured every two weeks for the first three months of treatment and monthly thereafter. Blood pressure, serum potassium and fluid retention should be monitored monthly. Dosing guidelines are available in the Product Monograph.
Zytiga™ is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Zytiga™ is also contraindicated in women who are or may potentially be pregnant. Zytiga™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Zytiga™ are described in the Product Monograph.
Priority Review Status was granted for the evaluation of Zytiga™ as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile is improved over existing therapies.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Zytiga™ in combination with prednisone is favourable for the treatment of metastatic prostate cancer (castration-resistant prostate cancer) in patients who have received prior chemotherapy containing docetaxel.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Abiraterone acetate, the medicinal ingredient of Zytiga™, is an androgen biosynthesis inhibitor. Zytiga™ is indicated with prednisone for the treatment of metastatic prostate cancer [castration-resistant prostate cancer (CRPC)] in patients who have received prior chemotherapy containing docetaxel. Zytiga™ is a selective inhibitor of the enzyme 17α-hydroxylase/C17, 20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in the testes, in the adrenal glands, and in the prostate tumour tissues. By inhibiting CYP17, Zytiga™ decreases serum testosterone and other androgens to levels lower than those achieved by the use of gonadotropin-releasing hormone (GnRH) agonists alone or by orchiectomy. Androgen-sensitive prostatic carcinoma has been shown to respond to treatment that decreases androgen levels.
Manufacturing Process and Process Controls
The drug substance, abiraterone acetate, is synthetically derived. The materials used in the manufacture of the drug substance are considered to be suitable and meet standards appropriate for their intended use. The manufacturing process consists of a multi-step synthesis. In-process controls performed during the manufacture were reviewed and are considered acceptable.
Characterization
The structure of abiraterone acetate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH)-established limits and/or were qualified from toxicology studies and batch analyses; and therefore considered to be acceptable.
Control of Drug Substance
The analytical methods and validation reports are considered satisfactory for all analytical procedures used for release and stability testing of the drug substance. The specifications are considered adequate to control the quality of the drug substance.
Data from the batch analysis were reviewed and are considered to be acceptable according to the specifications of the drug substance.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data, the proposed retest period, shelf-life and storage conditions for the drug substance are supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Each Zytiga™ tablet is off-white in colour, oval shaped, debossed with 'AA250', and contains 250 mg of abiraterone acetate. Zytiga™ 250 mg tablets are stored in high-density polyethylene bottles fitted with a polypropylene cap and contain 120 tablets per bottle.
The non-medicinal ingredients contained in the tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate and colloidal silicon dioxide.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of abiraterone acetate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
A detailed description of the manufacturing process was provided. The drug product manufacturing process uses conventional manufacturing techniques, namely: preblending; high shear wet granulation; wet milling; fluid bed drying; dry milling; blending; lubrication; and compression. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Data was provided from a single-dose, crossover comparative, bioequivalence study which compared two abiraterone acetate 250 mg tablet formulations manufactured at different sites; one produced for clinical trial purposes versus the other produced for commercial purposes. Results from the bioequivalence study did support a manufacturing site transfer for the means of commercial production.
Control of Drug Product
Zytiga™ is tested to verify that its identity, appearance, purity, content uniformity, assay, dissolution, particle size, levels of degradation products, drug-related impurities and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products are within acceptable limits. The validation process is considered to be complete.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, accelerated stability data submitted, the proposed shelf-life of 24-months is considered acceptable for the product when stored at 15-30°C.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment which are involved in the production of Zytiga™ are considered suitable for the activities and products manufactured. All proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations and are also compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Lactose monohydrate used in the manufacture of Zytiga™ is compliant with applicable bovine spongiform encephalopathy/transmissible spongiform encephalopathy (BSE/TSE) guidelines.
The magnesium stearate used in the manufacture of Zytiga™ is obtained exclusively from vegetable sources.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Zytiga™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
In vivo pharmacology studies demonstrated that abiraterone acetate (Zytiga™) is rapidly converted to abiraterone a specific and irreversible inhibitor of the CYP17 enzyme involved with the production of testosterone and other androgens within testicular, adrenal and prostatic tumour tissues. By suppressing the production of testosterone, androgen levels are reduced to levels lower than those achieved by castration which results in slowing down growth of prostatic tumours.
The in vivo effects of abiraterone acetate on the circulating hormone levels and organ weights were characterized in mice and rats. Abiraterone acetate reduced the weights of testes, ventral prostate, and seminal vesicles. These phenotypes correlated with a decreased level of plasma testosterone in both mice and rats.
Abiraterone had no physiologically relevant effect on the 'rapid' component of the delayed rectifier potassium current (Ikr) in the human ether-a-go-go gene (hERG)-transfected HEK293 cells up to a concentration of 27 µM. The half maximal inhibitory concentration (IC50) for abiraterone acetate was 12.2 µM and a very limited inhibitory effect (2%) was seen at a concentration of 1.3 µM. As abiraterone acetate is rapidly converted in vivo to abiraterone, the hERG inhibition by abiraterone acetate was considered of limited physiological relevance.
Safety Pharmacology
Abiraterone acetate had no relevant effects on the central nervous system (CNS) when administered to male rats as a single oral dose up to 400 mg/kg.
In a cardiovascular safety study, no haemodynamic and electrocardiographic changes were noted in telemetered male monkeys dosed with abiraterone acetate up to 2,000 mg/kg.
In a respiratory safety study in the rat, no relevant respiratory effects were noted after dosing with abiraterone acetate up to 2,000 mg/kg.
No gastric irritation was observed when abiraterone acetate was administered as a single oral dose to male mice at 800 mg/kg.
3.2.2 Pharmacokinetics
Absorption
Abiraterone acetate and abiraterone were found to have a low apparent permeability in cell culture studies.
In all animal species investigated, peak plasma concentrations of abiraterone were rapidly reached, in most cases within 1 to 2 hours following dose administrations. At higher dose levels, peak concentrations occurred later and concentrations showed a plateau up to 9 hours after dosing. The terminal half-life was 2 hours in mice, 1.29 to 3.82 hours in rats, and 2.6 to 11.8 hours in monkeys.
After single dosing, there were no gender differences in mice and monkeys, whereas in rats, exposure to abiraterone in males was markedly higher than in females.
Upon repeated administration, exposure markedly decreased in both male and female mice, in comparison with single administration. In rats, exposure decreased markedly in males and remained constant or increased up to 2-fold in females, with exposure in males still being higher than in females. In monkeys exposure to abiraterone remained fairly comparable upon repeated administration of abiraterone acetate.
In general, after both single and repeated administration of abiraterone acetate, plasma levels of abiraterone increased with increasing dose levels of abiraterone acetate, but less than proportional to the dose. At the highest dose levels of abiraterone acetate investigated, no significant increase in plasma levels of abiraterone was observed with an increase of the abiraterone acetate dose. This indicates saturation of absorption or solubility limitations of abiraterone acetate.
Distribution
Upon entry into circulation, abiraterone acetate was rapidly converted to abiraterone (<5 min) and widely distributed with maximum serum levels detected 1 to 2 hours post-dose. Organs showing the highest radioactive concentrations following administration of radio-labelled abiraterone acetate were the liver, adrenal glands, kidney (cortex), and gastrointestinal tract.
Metabolism
In all species tested, the metabolic profile of abiraterone acetate was quite similar. Following oral administration of radio-labelled abiraterone acetate, abiraterone acetate was shown to be hydrolyzed rapidly to abiraterone. This reaction was not mediated via cytochrome P450 (CYP) enzyme, but rather hypothesized to occur via an unidentified esterase(s). Abiraterone then undergoes metabolism including sulphation, hydroxylation, glucuronidation and oxidation primarily in the liver. Multiple families of enzymes were involved [CYP, uridine 5'-diphospho-glucuronosyltransferase (UGT) and sulfotransferase (SULT)] in the latter reactions which results in the formation of two major metabolites, abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), each accounting for approximately 43% of total radioactivity.
Elimination
Within 24 hours 86% of the administered dose was excreted primarily through the fæces. There was no difference noted in routes and rates of excretion between male and female rats.
3.2.3 Toxicology
Single-Dose Toxicity
The single-dose toxicity studies in mice (800 mg/kg), rats (400 mg/kg) and monkeys (2,000 mg/kg) demonstrated that initial doses of abiraterone acetate were well-tolerated, safe with no treatment related mortalities or abnormalities, at doses and exposures higher than the clinically recommended dose in humans.
Repeat-Dose Toxicity
In 13-and 26-week repeat-dose studies conducted in rats, and 13- and 39-week repeat-dose studies conducted in monkeys, circulating testosterone levels were shown to have been significantly reduced following administration of abiraterone acetate. Furthermore, morphological and/or histopathological changes were observed in the reproductive organs which included, aspermia/hypospermia, atrophy/weight reductions in the male genital tract organs (seminal vesicles, prostate, epididymis) and testes. Additionally, adrenal gland hypertrophy, leydig cell hyperplasia, pituitary gland hyperplasia and mammary gland hyperplasia were also noted. These observed changes in the reproductive organs and androgen-sensitive organs were consistent with the pharmacodynamic properties of abiraterone. All the above treatment-related changes were partially or fully reversible after a 4-week recovery period.
After chronic treatment from 13 weeks onward, hepatocellular hypertrophy and bile duct/oval cell hyperplasia, associated with increased serum alkaline phosphatase and/or total bilirubin levels, were seen in rat and monkey livers. After a 4-week recovery period, serum parameters reversed, whereas bile duct/oval cell hyperplasia persisted.
A dose-dependent increase in cataracts was also observed after 26 weeks of treatment in rats. These changes were irreversible after a 4-week recovery period. In contrast, cataracts were not observed in monkeys after 13 or 39 weeks of treatment. Moreover, the incidence of cataract formation in the Phase III pivotal study (see section 3.3.3 Clinical Efficacy) was comparable to that of the placebo-treated group.
Carcinogenicity and Genotoxicity
Abiraterone acetate and abiraterone were devoid of genotoxic potential in the standard panel of genotoxicity tests, including an in vitro bacterial reverse mutation assay (the Ames test), an in vitro mammalian chromosome aberration test (using human lymphocytes) and an in vivo rat micronucleus assay.
Reproductive and Developmental Toxicity
Neither developmental nor reproductive toxicology studies were conducted with abiraterone acetate, however, in animal toxicology studies, the majority of the toxicity was observed in the reproductive organs which relates to the pharmacodynamic properties of abiraterone interfering with CYP17 and thus steroidogenesis. In male, rats and monkeys, these effects were seen in the testes, prostate, seminal vesicles, and epidymidis and the mammary glands. In females, most notable changes were seen in the ovaries, but also in the uterus, cervix, and vagina. Associated with the effect on steroidogenesis is the adrenocorticotropic hormone (ACTH)-related adrenocortical hypertrophy and hypertrophy/hyperplasia of the pituitary gland. These exaggerated pharmacological effects were partially to fully reversible after a 4-week recovery period.
Mammary Gland
Male mammary gland hyperplasia, inflammation and fibrosis were observed in the 28-day and 13-week monkey studies but not in the 39-week monkey study. In addition, these changes did not entirely reverse within the 28-day treatment-free recovery period.
Liver
Another noted target organ is the liver as evidenced by hepatocellular hypertrophy associated with bile duct hyperplasia, and serum increases of alkaline phosphatase (ALP) and total bilirubin. These findings were seen in the pivotal rat and monkey studies. These changes were partially to fully reversible after a 28-day recovery period.
Heart
Although infrequent, ventricular premature complexes were observed on electrocardiograms (ECGs) of monkeys in a 39-week study. These observed arrhythmias were considered of limited value given there were no further abnormalities found at the end of treatment. In addition, these cardiovascular effects did not correspond to an abiraterone peak plasma effect. Also, no ECG of blood pressure effects were observed in the 13-week study conducted in monkeys. However, the monkeys used in both of the 13- and 39-week studies were relatively young, thus their hearts were healthier than would be found in older patients with metastatic prostate cancer previously treated with docetaxel. Based on the mechanism of action of Zytiga™, pre-existing heart conditions may be exacerbated with use of this drug. Patients with clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or left ventricular ejection fraction <50% or New York Heart Association Class III or IV heart failure were excluded from the pivotal study. Therefore a cautionary statement has been inserted in the Product Monograph for use of Zytiga™ in patients with a history of cardiovascular disease.
3.2.4 Summary and Conclusion
The main toxic effects observed in the non-clinical studies were related to the pharmacological activity (selective CYP17 inhibition) of abiraterone acetate affecting the animal's steroidogenesis, reproductive organs, as well as the adrenal, pituitary, and male mammary glands. Partially reversible bile duct changes were also seen in the rat and monkey studies along with reversible hepatocellular hypertrophy. Irreversible cataract formation was only observed in the rat studies. Toxicology data regarding a possible cardiotoxic effect was inconsistent and thereby inconclusive. Full disclosure of these findings has been made by the inclusion of appropriate statements in the Zytiga™ Product Monograph.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In terms of biomarkers assessing pharmacodynamic activity, levels of Prostate Specific Antigen (PSA) were used to determine the biological activity of this anti-cancer agent. In the clinical studies conducted, patients who received Zytiga™ treatment consistently demonstrated a significantly higher total PSA response rate compared with patients who received a placebo. Although monitoring of PSA levels is a well recognized biomarker, observed changes in PSA levels has not been shown to correlate with a clinical benefit in individual patients. Total testosterone and other androgens were therefore also assessed as indirect pharmacodynamic biomarkers and were regularly monitored as part of the clinical laboratory assessments. Treatment with Zytiga™ was shown to significantly suppress testosterone, dehydroepiandrosterone (DHEA), and androstenedione.
Androgen deprivation therapy has been associated with QTc prolongation. A cardiac study was conducted on 33 patients with metastatic CRPC who had been either medically or surgically castrated. At steady-state on day 1 of cycle 2, the QTc interval was significantly shortened at most time points, with a maximum decrease from baseline of mean 10.7 ms [90% confidence interval (CI) -14.8, -6.5] at 24 hours post-dosing. Therefore, Zytiga™ was not associated with QTc prolongation in the study population. However, the patients in this study were already androgen-deprived and androgen deprivation is known to be associated with QTc prolongation. In fact, the QTc interval average 435-440 ms at baseline and 57.6% of patients had baseline QTc values >450 ms prior to initiation of abiraterone acetate. Therefore, the results of this study cannot be extrapolated to non-castrated populations.
3.3.2 Pharmacokinetics
Absorption
Following oral administration Zytiga™, abiraterone acetate was absorbed through the intestine. Abiraterone acetate was then rapidly converted to abiraterone, an androgen biosynthesis inhibitor. The median time to reach peak plasma concentration (tmax) of abiraterone, in CRPC patients, was approximately 2 hours post-dose when given as 1,000 mg (4 x 250 mg tablets). The maximum pharmacodynamic effect of Zytiga™ was achieved approximately 12 hours post-dose. The Cmax and area under the curve (AUC) in CRPC patients were 216.5 ng/mL and 979 ng*h/mL, respectively. In addition, a large inter-patient variability was observed between healthy volunteers and CRPC patients.
There was also an important food effect associated with Zytiga™. Abiraterone's maximum drug concentration (Cmax) and plasma exposure increased up to 17- and 10-fold higher, respectively, when a single dose of Zytiga™ was administered with a high-fat meal compared to a fasted state and increased up to 7- and 5-fold higher, respectively, when a single dose of Zytiga™ was administered with a low-fat meal compared to a fasted state. The safety of these increased exposures when multiple doses of Zytiga™ are taken with food has not been assessed. This important food effect has been reflected in the Product Monograph. It is recommended that Zytiga™ must be taken on an empty stomach and that no solid or liquid food be consumed for at least 2 hours before taking Zytiga™ and for at least 1 hour following dose administration.
Distribution
Zytiga™ was highly bound to human plasma proteins (99.8%-99.9%), and mainly retained in the plasma component of the blood. The apparent central volume of distribution is approximately 5,630 L, suggesting that abiraterone extensively distributes to peripheral tissues. In vitro studies showed that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp). However, in vitro studies show that abiraterone acetate is an inhibitor of P-gp. No studies have been conducted with other transporter proteins.
Metabolism
Zytiga™ was metabolically cleared in the liver via several biotransformation mechanisms including sulphation, hydroxylation, oxidation and dehydration. A total of fifteen metabolites were detected in the human plasma samples, of which N-oxide abiraterone sulphate and abiraterone sulphate each represented approximately 43% of the total plasma volume. The formation of N-oxide abiraterone sulphate was predominately catalyzed by cytochrome P450 (CYP) 3A4 and human sulfotransferase (SULT2A1) while the formation of abiraterone sulphate was catalyzed solely by SULT2A1. These two metabolites were determined to be inactive, yet higher metabolite exposure is expected in patients with CRPC given these patients have higher exposure to abiraterone due to reduced clearance compared to healthy volunteers.
Elimination
Following oral administration of radioactive abiraterone acetate capsules, a mean total radioactive dose of 87.9% was recovered in the faeces and 5.3% was recovered in the urine. The major components in the faeces were unchanged abiraterone acetate and abiraterone at 55.3% and 22.3%, respectively. In the population pharmacokinetics study, it was noted that the clearance was decreased by 33% in patients with CRPC compared to healthy volunteers, suggesting a higher abiraterone exposure in CRPC patients.
Drug-Drug Interactions
Clinical data have shown that Zytiga™ is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Therefore, concomitant use of CYP2D6 substrates should be avoided or used with caution. Based on in vitro data, the active metabolite abiraterone is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors or inducers during Zytiga™ treatment should be avoided or used with caution.
Food-Drug Interactions
Administration of Zytiga™ with food significantly increased the absorption of abiraterone acetate. The efficacy and safety of Zytiga™ given with food has not been established. Therefore, Zytiga™ must not be taken with solid or liquid food.
3.3.3 Clinical Efficacy
The efficacy findings for Zytiga™ were derived primarily from one pivotal Phase III study. Other Phase II studies were also provided in support of the pivotal Phase III results.
The Phase III pivotal study was a multinational, multicentre, randomized, double-blind, placebo-controlled study conducted at 147 sites within the United States, Europe, Australia and Canada and enrolled a total of 1,195 patients. The primary efficacy endpoint of this study was to demonstrate whether treatment with Zytiga™ improved overall survival among men with metastatic CRPC (mCRPC) whose disease had progressed on or after 1 or 2 chemotherapy regimens, where at least one of which contained docetaxel.
The study design consisted of patients being randomly assigned in a 2:1 ratio. Patients received either Zytiga™ and prednisone [number of patients (n) = 797] or a placebo (n = 398). The study comprised screening period (within 14 days prior to Cycle 1 Day 1), a treatment period (until documented disease progression or unacceptable toxicity), and a follow-up period [follow-up every 3 months up to 60 months (5 years)]. While treatment was administered on a continuous schedule, each cycle of treatment was for a duration of 28 days. Safety and dosing compliance were evaluated during the Cycle 1 Day 15 visit, on Day 1 of each subsequent cycle, at treatment discontinuation if applicable, and at the end-of-study visit. One interim analysis was planned after approximately 534 deaths were observed and a final analysis was planned after observing 797 total deaths.
Results from the planned interim analysis (conducted after 552 deaths were observed) showed that 42% (333 of 797) of the patients treated with Zytiga™, compared with 55% (219 of 398) of patients treated with placebo, had died. A statistically significant improvement in median overall survival was seen in patients treated with Zytiga™ compared to a placebo (14.8 months and 10.9 months respectively; Hazard ratio = 0.646; 95% CI: 0.543 to 0.768; p<0.0001).
A final survival analysis was conducted when 775 deaths (97% of the planned number of deaths) were observed. Results from this analysis were consistent with those from the interim analysis. A total of 63% (501 of 797) of the patients treated with Zytiga™, compared with 69% (274 of 398) of patients treated with placebo, had died. The median overall survival observed with patients treated with Zytiga™ was 15.8 months compared to 11.2 months for patients treated with a placebo (Hazard ratio = 0.740; 95% CI; 0.638 to 0.859). Additionally, sub-group analyses also showed a consistent favourable survival effect for the patients treated with Zytiga™.
Results from the analyses of the secondary efficacy endpoints, that being time to prostate-specific antigen (PSA) progression, radiographic progression-free survival, and PSA response rate also demonstrated the same consistency in results. While PSA-based endpoints are not validated surrogate endpoints of clinical benefit in this patient population, patients receiving Zytiga™ demonstrated a significantly higher total PSA response rate, compared with patients receiving placebo: 38% versus 10% (p<0.0001). The median time to PSA progression was 10.2 months for patients treated with Zytiga™ and 6.6 months for patients treated with placebo. Furthermore, the median radiographic progression-free survival was 5.6 months for patients treated with Zytiga™ and 3.6 months for patients who received placebo. Furthermore, the efficacy results observed in the Phase II studies were consistent with those observed in the pivotal Phase III efficacy results.
Additional secondary endpoints of pain palliation and time to first skeletal event were analysed. The proportion of patients with pain palliation was statistically significantly higher in the Zytiga™ group than in the placebo group (44% versus 27%, p = 0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the Brief Pain Inventory - Short Form (BPI-SF) worst pain intensity score over the last 24 hours without any increase in analgesic usage score observed at two consecutive evaluations four weeks apart. Only patients with a baseline pain score of ≥4 and at least one post-baseline pain score were analyzed (N = 512) for pain palliation.
Pain progression was defined as an increase from baseline of ≥30% in the BPI-SF worst pain intensity score over the previous 24 hours without a decrease in analgesic usage score observed at two consecutive visits, or an increase of ≥30% in analgesic usage score observed at two consecutive visits. The time to pain progression at the 25th percentile was 7.4 months in the Zytiga™ group, versus 4.7 months in the placebo group. The time to first skeletal-related event at the 25th percentile in the Zytiga™ group was twice that of the control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone.
3.3.4 Clinical Safety
During the Phase III pivotal study (see section 3.3.3 Clinical Efficacy) the most common adverse events (AEs) reported with Zytiga™ compared to placebo were myopathy, joint pain or discomfort, peripheral oedema, hot flush, diarrhea, hypokalaemia, urinary tract infection, and cough. The most common serious adverse events (SAEs) observed were urinary tract infection, bone fracture, and hypokalaemia. The most common Zytiga™ AEs leading to clinical intervention were elevated aspartate aminotransferase (AST) enzymes, elevated alanine transaminase (ALT) enzymes, hypokalaemia, urinary tract infection, hypertension, congestive heart failure, and angina pectoris. The most common AEs which resulted in drug discontinuation were elevated AST enzymes and cardiac failure.
Zytiga™ may cause hypertension, hypokalaemia and fluid retention due to the pharmacodynamic consequences of its mechanism of action. Generally, these effects caused by mineralocorticoid excess, can be successfully managed medically. The concomitant use of a corticosteroid reduces the incidence and severity of these AEs. In addition, a further reduction of these AEs can be achieved by ensuring hypertension is well-controlled and hypokalaemia is corrected prior to initiating treatment with Zytiga™ as recommended within the Product Monograph. Furthermore, it is also suggested that blood pressure, serum potassium and fluid retention be monitored monthly once treatment has begun.
Marked increases in liver enzymes leading to clinical intervention in a few patients indicate that Zytiga™ is hepatotoxic. The exposure to abiraterone is increased in patients with moderate hepatic impairment. The safety of Zytiga™ in patients with severe hepatic impairment has not been evaluated. In the Product Monograph, Zytiga™ is not recommended to be used in patients with pre-existing moderate or severe hepatic impairment. The Monitoring and Laboratory Tests section recommends that serum transaminases and bilirubin should be measured prior to starting treatment every two weeks for the first three months of treatment and monthly thereafter. There is also an acceptable dose adjustment strategy for patients developing hepatic impairment during treatment.
Zytiga™ is expected to produce changes in maternal hormone levels that could affect foetal development. To avoid inadvertent exposure to the foetus, the Product Monograph indicates that Zytiga™ is contraindicated in women who are or may potentially be pregnant. Women who are pregnant or women who may be pregnant should not handle Zytiga™ without protection, for example (e.g.), gloves.
An increase in the number of bone fractures was reported within Zytiga™-treated patients (5.9%) compared to the placebo-treated patients (2.3%) within the Phase III pivotal study. This is consistent with the association of androgen-deprivation therapy with decreased bone density which may lead to a higher incidence of skeletal fractures. "Fractures" has been listed as a significant AE within the Product Monograph.
The Product Monograph addresses the potential safety concerns in regards to potential drug-drug interactions with strong inhibitors and inducers of CYP3A4 and with drugs activated or metabolized by CYP2D6.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review Status was granted for the evaluation of Zytiga™ as it appeared to provide substantial evidence of increased clinical efficacy such that the overall benefit/risk profile was improved over existing therapies.
Efficacy findings derived mainly from one pivotal Phase III study, in addition to supportive studies, demonstrated that treatment with Zytiga™ in combination with prednisone/prednisolone improves survival among men with mCRPC whose disease had progressed on or after one or two chemotherapy regimens, where at least one treatment contained docetaxel. Overall, the efficacy findings were statistically and clinically significant in support of the use of Zytiga™ as part of the treatment plan. Sub-group analyses also showed a consistent favourable survival effect for patients treated with Zytiga™. The efficacy results therefore support the intended indication and the target population.
The most common AEs observed with Zytiga™ compared to placebo were myopathy, joint pain or discomfort, peripheral oedema, hot flush, diarrhoea, hypokalaemia, urinary tract infection, and cough. The most common SAEs observed were urinary tract infection, bone fracture, and hypokalaemia. In addition, marked increases in liver enzymes leading to clinical intervention in a few patients suggest that Zytiga™ is hepatotoxic. To reduce the risk of hepatotoxicity, Zytiga™ is not recommended to be used in patients with pre-existing moderate or severe hepatic impairment. In addition, regular monitoring of liver function tests is recommended and a dose adjustment strategy has been created for patients developing hepatic impairment during treatment.
In conclusion, Zytiga™ is an efficacious oral medication that improves the overall survival of patients with prostate cancer when compared to a placebo. Moreover, Zytiga™ is not associated with severe side effects as observed with cytotoxic chemotherapy. The side effects associated with Zytiga™ such as hypertension, hypokalaemia, and peripheral oedema are all clinically manageable. Finally, the concomitant use of corticosteroid can reduce the frequency and severity of these side effects. The labelling information for Zytiga™ also accurately reflects the safety, efficacy, and quality assessments associated with its administration. The benefit/risk profile for Zytiga™ for the proposed indication is therefore favourable. To withhold approval for Zytiga™ would prevent mCRPC patients of benefitting from a relatively safe drug that has the potential to improve their overall survival.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Zytiga™, in combination with prednisone, is favourable for the treatment of metastatic prostate cancer (castration-resistant prostate cancer) in patients who have received prior chemotherapy containing docetaxel. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: ZytigaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-12-09 |
| Request for priority status | |
| Filed: | 2010-11-12 |
| Approval issued by the Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS): | 2010-12-23 |
| Submission filed: | 2010-12-23 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-01-28 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2011-05-13 |
| Quality Evaluation complete: | 2011-07-25 |
| Clinical Evaluation complete: | 2011-07-26 |
| Biostatistics Evaluation complete: | 2011-06-20 |
| Labelling Review complete: | 2011-07-26 |
| Notice of Compliance issued by Director General: | 2011-07-26 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZYTIGA | 02371065 | JANSSEN INC | ABIRATERONE ACETATE 250 MG |